1. Field of the Invention
This invention relates to treatments of addictive disorders, such as alcoholism, more particularly this invention relates to the treatment of the symptoms of alcoholic withdrawal.
2. State of the Art
Alcoholism is a common health problem in the United States. Millions suffer from the disease in one degree or another. The results of the disease are billions of dollars spent on treatment, rehabilitation, and more billions wasted on lost man hours at work and petty crimes committed by inebriated individuals. The social cost to the families and acquaintances of alcoholics is incalculable.
Alcoholism is a syndrome consisting of 2 phases: problem drinking and alcohol addiction. Problem drinking is the repetitive use of alcohol, often to alleviate anxiety or solve other emotional problems. Alcohol addiction is a true addiction similar to that which occurs following the repeated use of other sedative-hypnotics.
40% of Japanese have aldehyde dehydrogenase deficiency and are more susceptible to the effects of alcohol.
The signs of alcoholic intoxication are the same as those of overdosage with any other central nervous system depressant: drowsiness, errors of commission, psyomotor dysfunction, disinhibition, dysarthia, ataxia, and nystagmus.
There is a wide spectrum of manifestations of alcoholic withdrawal, ranging from anxiety, decreased cognition, and tremulousness through increasing irritability and hyperactivity to full-blown delirium tremens. The latter is an acute organic psychosis that is usually manifested within 24-72 hours after the last drink (but may occur up to 7-10 days later). It is characterized by mental confusion, tremor, sensory hyperacuity, visual hallucinations (often of snakes, bugs, etc.), autonomic hyperactivity, diaphoresis, dehydration, electrolyte disturbances, hypokalemia hypomagnesemia, seizures and cardiovascular abnormalities. The acute withdrawal syndrome is often completely unexpected and occurs when the patient has been hospitalized for some unrelated problem and presents as a diagnostic problem. Suspect alcohol withdrawal in every unexplained delirium. Seizures occur early (the first 24 hours) and are more prevalent in persons who have a history of withdrawal syndromes. The mortality rate from delirium tremors has steadily decreased with early diagnosis and improved treatment.
In addition to the immediate withdrawal symptoms, there is evidence of persistent long-term one, including sleep disturbances, anxiety, depression, excitability, fatigue, and emotional volatility. These symptoms may persist for 3-12 months, and in some cases they become chronic.
Alcoholic (Organic) Hallucinosis occurs either during heavy drinking or on withdrawal and is characterized by a paranoid psychosis.
According to the National Institute on Alcohol Abuse and Alcoholism new treatments and new medical agents to help provide such new treatments are needed for the additional factors they have identified as effects of alcoholism including: 1) agents to decrease the desire to drink by attenuating alcohol craving and blocking the euphoric effect (reward) derived from drinking alcohol; 2) agents to induce sobriety in intoxicated individuals; 3) mechanisms of alcohol intoxication and development of a clinically useful antagonist of alcohol-intoxication. (A significant number of people die each year from alcohol overdoses. In order to effectively treat this problem, medications developed based on the mechanisms of the depressant effects of alcohol are needed); 4) development of medications to improve cognitive dysfunction in alcoholic dementia/Korsakoff's psychosis. (Progress in this area would lead to enrichment in quality of life of alcoholics as well as reduction in costs of long-term institutionalization. Recent studies have shown that serotonin reuptake inhibitors can improve memory to a clinically meaningful degree in some patients with alcohol-induced amnesia); 5) development of medications to treat alcoholic liver disease and other alcohol related, end-organ diseases. (In reducing the high mortality from alcoholic hepatitis, potential medications include that affect the production or clearance of cytokines, prevent other causes of necrosis/inflammation, and avert the progression of fibrosis. Other potential agents are those with potential utility in treatment of portal hypertension and alcohol-induced pancreatic disease); 6) determination of appropriate medicational strategy based on severity of acute alcohol withdrawal; 7) mechanisms of alcohol dependence, Psychological and physical dependence on alcohol are presumed to contribute to continued drinking and relapse. (Understanding the cellular and molecular mechanisms of craving for alcohol after chronic use and how it might be reduced is needed); 8) strategies to reduce the organ damage caused by chronic alcohol abuse. (This damage is mostly to the liver, brain, cardiovascular system, and pancreas. Research is needed into the underlying mechanism of alcoholic hepatitis, brain damage portal hypertension, cardiomyopathy, and pancreatitis. Understanding these mechanisms will lead to the development of medications that are useful in alleviating or counter-acting alcohol induced tissue injury, such as free radical scavengers, cognitive enchanters, and transplantation). It is clear that new approaches to the treatment of alcoholism are needed.
There have been many approaches to the problem, including the psychological, such as counseling and self help programs such as Alcoholics Anonymous and drug treatment such as Antibuse. None have been completely successful either in stopping all alcoholics from drinking or from keeping a non-drinking alcoholic from starting to drink again.
One promising approach to the treatment of acute intoxication is the administration of Nicotinamide-adenine Dinucleotide (NAD), also known as Diphospho Pyridine Neucleotide (DPN) and Coenzyme I to the sufferer. This allows the alcohol dehydrogenase found throughout the cytoplasm to function to oxidize alcohol in other places in the body other than the liver.
The use of pyridine nucleotides is known to facilitate the treatment of several diverse diseases. For example, U.S. Pat. No. 3,412,190 to O'Holleran teaches the use of NAD for the lipids in the blood stream. They have also been used to treat alcoholism. Canadian Patent 670,909 teaches the use of NAD for the control the symptoms of acute alcoholism.
NAD is metabolized in the body rapidly. It would be advantageous to provide a slower metabolizing form of NAD for the recovering alcoholic. NAD also comes in a phosphated form, NADP having slightly different activity and resistance to metabolic deactivation. It would be advantageous to allow the alcoholic sufferer to be dosed with both NAD and NADP to increase the spectrum of the pharmacological action. Finally, NAD is not completely absorbed by the gastric acid intestinal mucosa. It would be advantageous to provide a form of completely absorbed NAD that could be orally administered.